Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Presence of centromeric but absence of telomeric group B KIR haplotypes in stem cell donors improve leukaemia control after HSCT for childhood ALL

Abstract

Although allogeneic hematopoietic stem-cell transplantation (HSCT) provides high cure rates for children with high-risk acute lymphoblastic leukaemia (ALL), relapses remain the main cause of treatment failure. Whereas donor killer cell immunoglobulin-like receptor (KIR) genotype was shown to impact on relapse incidence in adult myeloid leukaemia similar studies in paediatric ALL are largely missing. Effect of donor KIR genotype on transplant outcome was evaluated in 317 children receiving a first myeloablative HSCT from an HLA-matched unrelated donor or sibling within the prospective ALL-SCT-BFM-2003 trial. Analysis of donor KIR gene polymorphism revealed that centromeric presence and telomeric absence of KIR B haplotypes was associated with reduced relapse risk. A centromeric/telomeric KIR score (ct-KIR score) integrating these observations correlated with relapse risk (hazard ratio (HR) 0.58; P = 0.002) while it had no impact on graft-versus-host disease or non-relapse mortality. In multivariable analyses ct-KIR score was associated with reduced relapse risk (HR 0.58; P = 0.003) and a trend towards improved event-free survival (HR 0.76; P = 0.059). This effect proved independent of MRD level prior to HSCT. Our data suggest that in children with ALL undergoing HSCT after myeloablative conditioning, donor selection based on KIR genotyping holds promise to improve clinical outcome by decreasing relapse risk and prolonged event-free survival.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Peters C, Schrappe M, von Stackelberg A, Schrauder A, Bader P, Ebell W, et al. Stem-cell transplantation in children with acute lymphoblastic leukemia: A prospective international multicenter trial comparing sibling donors with matched unrelated donors-The ALL-SCT-BFM-2003 trial. J Clin Oncol. 2015;33:1265–74.

    Article  CAS  Google Scholar 

  2. Babor F, Fischer JC, Uhrberg M. The role of KIR genes and ligands in leukemia surveillance. Front Immunol. 2013;4:27.

    Article  Google Scholar 

  3. Manser AR, Weinhold S, Uhrberg M. Human KIR repertoires: shaped by genetic diversity and evolution. Immunol Rev. 2015;267:178–96.

    Article  CAS  Google Scholar 

  4. Cooley S, Trachtenberg E, Bergemann TL, Saeteurn K, Klein J, Le CT, et al. Donors with group B KIR haplotypes improve relapse-free survival after unrelated hematopoietic cell transplantation for acute myelogenous leukemia. Blood. 2009;113:726–32.

    Article  CAS  Google Scholar 

  5. Cooley S, Weisdorf DJ, Guethlein LA, Klein JP, Wang T, Le CT, et al. Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. Blood. 2010;116:2411–9.

    Article  CAS  Google Scholar 

  6. Cooley S, Weisdorf DJ, Guethlein LA, Klein JP, Wang T, Marsh SG, et al. Donor killer cell Ig-like receptor B haplotypes, recipient HLA-C1, and HLA-C mismatch enhance the clinical benefit of unrelated transplantation for acute myelogenous leukemia. J Immunol. 2014;192:4592–4600.

    Article  CAS  Google Scholar 

  7. Oevermann L, Michaelis SU, Mezger M, Lang P, Toporski J, Bertaina A, et al. KIR B haplotype donors confer a reduced risk for relapse after haploidentical transplantation in children with ALL. Blood. 2014;124:2744–7.

    Article  CAS  Google Scholar 

  8. Sobecks RM, Wang T, Askar M, Gallagher MM, Haagenson M, Spellman S, et al. Impact of KIR and HLA genotypes on outcomes after reduced-intensity conditioning hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2015;21:1589–96.

    Article  CAS  Google Scholar 

  9. Locatelli F, Merli P, Pagliara D, Li Pira G, Falco M, Pende D et al. Outcome of children with acute leukemia given HLA-haploidentical HSCT after alphabeta T-cell and B-cell depletion. Blood https://doi.org/10.1182/blood-2017-04-779769 2017.

    Article  CAS  Google Scholar 

  10. Uhrberg M, Parham P, Wernet P. Definition of gene content for nine common group B haplotypes of the Caucasoid population: KIR haplotypes contain between seven and eleven KIR genes. Immunogenetics. 2002;54:221–9.

    Article  CAS  Google Scholar 

  11. Vilches C, Castano J, Gomez-Lozano N, Estefania E. Facilitation of KIR genotyping by a PCR-SSP method that amplifies short DNA fragments. Tissue Antigens. 2007;70:415–22.

    Article  CAS  Google Scholar 

  12. Prentice RL, Kalbfleisch JD, Peterson AV Jr., Flournoy N, Farewell VT, et al. The analysis of failure times in the presence of competing risks. Biometrics. 1978;34:541–54.

    Article  CAS  Google Scholar 

  13. Gray R. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16:1141–54.

    Article  Google Scholar 

  14. Fine J, Gray R. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.

    Article  Google Scholar 

  15. Bachanova V, Weisdorf DJ, Wang T, Marsh SG, Trachtenberg E, Haagenson MD, et al. Donor KIR B genotype improves progression-free survival of non-Hodgkin lymphoma patients receiving unrelated donor transplantation. Biol Blood Marrow Transplant. 2016;22:1602–7.

    Article  Google Scholar 

  16. Lee SJ, Klein J, Haagenson M, Baxter-Lowe LA, Confer DL, Eapen M, et al. High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood. 2007;110:4576–83.

    Article  CAS  Google Scholar 

  17. Woolfrey A, Klein JP, Haagenson M, Spellman S, Petersdorf E, Oudshoorn M, et al. HLA-C antigen mismatch is associated with worse outcome in unrelated donor peripheral blood stem cell transplantation. Biol Blood Marrow Transplant. 2011;17:885–92.

    Article  CAS  Google Scholar 

  18. Pidala J, Lee SJ, Ahn KW, Spellman S, Wang HL, Aljurf M, et al. Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated allogeneic hematopoietic cell transplantation. Blood. 2014;124:2596–606.

    Article  CAS  Google Scholar 

  19. Kollman C, Spellman SR, Zhang MJ, Hassebroek A, Anasetti C, Antin JH, et al. The effect of donor characteristics on survival after unrelated donor transplantation for hematologic malignancy. Blood. 2016;127:260–7.

    Article  CAS  Google Scholar 

  20. Ljungman P, Brand R, Hoek J, de la Camara R, Cordonnier C, Einsele H, et al. Donor cytomegalovirus status influences the outcome of allogeneic stem cell transplant: a study by the European group for blood and marrow transplantation. Clin Infect Dis. 2014;59:473–81.

    Article  Google Scholar 

  21. Bader P, Kreyenberg H, von Stackelberg A, Eckert C, Salzmann-Manrique E, Meisel R, et al. Monitoring of minimal residual disease after allogeneic stem-cell transplantation in relapsed childhood acute lymphoblastic leukemia allows for the identification of impending relapse: results of the ALL-BFM-SCT 2003 trial. J Clin Oncol. 2015;33:1275–84.

    Article  CAS  Google Scholar 

  22. Lee SJ, Klein JP, Barrett AJ, Ringden O, Antin JH, Cahn JY, et al. Severity of chronic graft-versus-host disease: association with treatment-related mortality and relapse. Blood. 2002;100:406–14.

    Article  CAS  Google Scholar 

  23. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295:2097–2100.

    Article  CAS  Google Scholar 

  24. Ruggeri L, Mancusi A, Capanni M, Urbani E, Carotti A, Aloisi T, et al. Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value. Blood. 2007;110:433–40.

    Article  CAS  Google Scholar 

  25. Mehta RS, Rezvani K. Can we make a better match or mismatch with KIR genotyping? Hematology Am Soc Hematol Educ Program. 2016;2016:106–18.

    Article  Google Scholar 

  26. Leung W. Use of NK cell activity in cure by transplant. Br J Haematol. 2011;155:14–29.

    Article  CAS  Google Scholar 

  27. Leung W, Iyengar R, Turner V, Lang P, Bader P, Conn P, et al. Determinants of antileukemia effects of allogeneic NK cells. J Immunol. 2004;172:644–50.

    Article  CAS  Google Scholar 

  28. Venstrom JM, Pittari G, Gooley TA, Chewning JH, Spellman S, Haagenson M, et al. HLA-C-dependent prevention of leukemia relapse by donor activating KIR2DS1. New Engl J Med. 2012;367:805–16.

    Article  CAS  Google Scholar 

  29. Bari R, Rujkijyanont P, Sullivan E, Kang G, Turner V, Gan K, et al. Effect of donor KIR2DL1 allelic polymorphism on the outcome of pediatric allogeneic hematopoietic stem-cell transplantation. J Clin Oncol. 2013;31:3782–90.

    Article  CAS  Google Scholar 

  30. Stringaris K, Adams S, Uribe M, Eniafe R, Wu CO, Savani BN, et al. Donor KIR Genes 2DL5A, 2DS1 and 3DS1 are associated with a reduced rate of leukemia relapse after HLA-identical sibling stem cell transplantation for acute myeloid leukemia but not other hematologic malignancies. Biol Blood Marrow Transplant. 2010;16:1257–64.

    Article  CAS  Google Scholar 

  31. Kroger N, Binder T, Zabelina T, Wolschke C, Schieder H, Renges H, et al. Low number of donor activating killer immunoglobulin-like receptors (KIR) genes but not KIR-ligand mismatch prevents relapse and improves disease-free survival in leukemia patients after in vivo T-cell depleted unrelated stem cell transplantation. Transplantation. 2006;82:1024–30.

    Article  Google Scholar 

  32. Cooley S, Miller JS. “Self”-reflection by KIR. Blood. 2009;114:2–3.

    Article  CAS  Google Scholar 

  33. Pfeiffer M, Schumm M, Feuchtinger T, Dietz K, Handgretinger R, Lang P. Intensity of HLA class I expression and KIR-mismatch determine NK-cell mediated lysis of leukaemic blasts from children with acute lymphatic leukaemia. Br J Haematol. 2007;138:97–100.

    Article  Google Scholar 

  34. Chen C, Busson M, Rocha V, Appert ML, Lepage V, Dulphy N, et al. Activating KIR genes are associated with CMV reactivation and survival after non-T-cell depleted HLA-identical sibling bone marrow transplantation for malignant disorders. Bone Marrow Transplant. 2006;38:437–44.

    Article  CAS  Google Scholar 

  35. Symons HJ, Leffell MS, Rossiter ND, Zahurak M, Jones RJ, Fuchs EJ. Improved survival with inhibitory killer immunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors after nonmyeloablative, HLA-haploidentical bone marrow transplantation. Biol Blood Marrow Transplant. 2010;16:533–42.

    Article  Google Scholar 

  36. Furst D, Muller C, Vucinic V, Bunjes D, Herr W, Gramatzki M, et al. High-resolution HLA matching in hematopoietic stem cell transplantation: a retrospective collaborative analysis. Blood. 2013;122:3220–9.

    Article  Google Scholar 

  37. Horan J, Wang T, Haagenson M, Spellman SR, Dehn J, Eapen M, et al. Evaluation of HLA matching in unrelated hematopoietic stem cell transplantation for nonmalignant disorders. Blood. 2012;120:2918–24.

    Article  CAS  Google Scholar 

  38. Wilson MJ, Torkar M, Haude A, Milne S, Jones T, Sheer D, et al. Plasticity in the organization and sequences of human KIR/ILT gene families. Proc Natl Acad Sci USA. 2000;97:4778–83.

    Article  CAS  Google Scholar 

  39. Martin AM, Kulski JK, Gaudieri S, Witt CS, Freitas EM, Trowsdale J, et al. Comparative genomic analysis, diversity and evolution of two KIR haplotypes A and B. Gene. 2004;335:121–31.

    Article  CAS  Google Scholar 

  40. van Bergen J, Trowsdale J. Ligand specificity of Killer cell Immunoglobulin-like receptors: a brief history of KIR. Front Immunol. 2012;3:394.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank all parents who gave their consent to use the biological material from their minors. This work was supported by the Deutsche Krebshilfe e.V. (M.U., R.M., and A.B.) (project 110351), the Forschungskommission of the Medical Faculty of the Heinrich-Heine University Düsseldorf (F.B.), and the TRANSAID - Stiftung fuer krebskranke Kinder (F.B.). The current affiliation of M.Si. is Department of Pediatrics and Mother and Child Center, Hospital Neuwerk, Mönchengladbach, Germany.

Author contributions

F.B., A.M., J.M., C.E. and N.S. performed the experiments; M.S., M.A., G.C., T.F., B.G., T.G., P.A.H., B.K., P.L., M.M., I.M., J.M., L.O., H.P., F.R.S., M.S., D.S., B.S., W.W., G.E., M.Z., M.S., A.B. and P.B. provided samples and conducted data the analysis and interpretation, and participated in patient care; E.G. and U.P. designed and performed the bioinformatic analyses; F.B., C.P., M.U. and R.M. wrote the manuscript, designed and directed the study; and all authors contributed to the research and approved the final manuscript.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Florian Babor, Markus Uhrberg or Roland Meisel.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Babor, F., Peters, C., Manser, A.R. et al. Presence of centromeric but absence of telomeric group B KIR haplotypes in stem cell donors improve leukaemia control after HSCT for childhood ALL. Bone Marrow Transplant 54, 1847–1858 (2019). https://doi.org/10.1038/s41409-019-0543-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-019-0543-z

This article is cited by

Search

Quick links